Summary Cancerous Inhibitor of Protein Phosphatase 2A (CIP2A), the protein encoded by the oncogene KIAA1524, inhibits the tumor suppressor activity of PP2A in human malignancies. CIP2A overexpression has been found in over 70% of tumor patient samples in the majority of human malignancies, including human head and neck squamous cell carcinoma, colon cancer, gastric cancer, breast cancer, prostate cancer and lung cancer. This makes CIP2A one of the most frequently overexpressed oncoproteins in all cancers. It has been shown that CIP2A is required for the malignant cellular growth and for in vivo tumor formation, by inhibiting PP2A's tumor suppressor activities towards several oncoproteins, including the oncogenic transcription factor c- Myc. Since it is non-essential for adult cells but required for tumoregenesis, CIP2A has become a highly significant drug target for cancer therapy. Knowing the 3D structure of CIP2A is essential for understanding how CIP2A functions and how to develop CIP2A inhibitors for cancer treatment. In this proposal, we aim to determine the first crystal structure of CIP2A and to reveal how it interacts with the regulatory B56 subunit of PP2A.